CXCL10 regulates heterogenity of the CD8+ T cell response and viral set point during chronic infection

CD8+ T cell responses to chronic infection are sustained by stem-like cells, which differentiate into effector-like cells mediating some level of pathogen control; however persistent antigen progressively impairs their effector functions. Understanding the molecular control of stem-like cell differentiation to improve durability of functional T cell responses has important therapeutic implications. Here, we found that the chemokine receptor CXCR3 was highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulated the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 was produced by inflammatory monocytes and fibroblasts of the splenic red pulp where it granted stem-like cells access to signals promoting differentiation and limited their exposure to pro-survival niches in the white pulp. Consequently, the magnitude of functional CD8+ T cell responses was greater in Cxcl10-/- mice and was associated with a lower viral set point. Four CD8+ T cell subsets distinguished based on the Ly108, CX3CR1 and CD101 expression sorted from WT or Cxcl10-/- are analyzed. Each subset has at least 3 biological replicates